Role of insulin-like growth factor (IGF) signalling pathway in cancers of the head and neck.
Head and neck squamous cell carcinomas, or oral cancer, is the sixth most common cancer globally and is a significant cause of morbidity and mortality. The incidence of oral cancer is rising annually and though there have been advances inresearch and treatment, there has been no improvement of patient survival rates. Additionally, no specific marker is in routine use to predict the clinical behaviour of oral squamous cell carcinoma (OSCC).
In recent years, aberrant expression of growth factor receptor systems and dysregulation of downstream cell signaling molecules has been reported in a wide range of epithelial tumours including oral cancer. The insulin-like growth factor (IGF) system is well documented to have a critical role in growth and development and is implicated in tumourigenesis and progression. The IGF system consists of two ligands, IGF-I and IGF-II and six types of high-affinity IGF binding proteins, IGFBP-1 to -6. Both IGF-I and -11 mediate their biological effects via a cell membrane-bound receptor, IGF-1R. Over-expression of IGF-I, IGF-II and IGF-IR, or combinations of these, has been noted in a wide variety of carcinomas and is thought to modulate tumour cell motility, adhesion as well as influence angiogenesis.
The role of IGF in the development of oral carcinomas is less clear. The aim of this study was to investigate the expression, and roles, of components of the IGF system in OSCC ex vivo and in vitro. Firstly, the relationship between serum levels of IGF-I and its binding proteins in patients with oral cancer was studied. Blood samples were taken and the plasma was analysed. Cancer patients had low levels of IGF-I, but high levels of IGFBP-1 and -2 compared to control patients. Secondly, we decided to characterise IGF-I, IGF-II, and IGF-1R by investigating their expression and function in human oral epithelial cancer cell lines and normal cells maintained in short-term culture. Tumour cells over-expressed IGF-II and IGF-1 R genes and protein compared to normal cells, as determined by western blotting, immunocytochemistry and DNA manipulation techniques. This pattern of over-expression was also observed in oral biopsy material taken from oral cancer patients, as detected by northem blotting and immunohistology. Thirdly, the importance between increased IGF-1 R expression and malignant transformation was studied by looking at IGF signaling mechanisms in normal oral epithelial cells. We found that IGF-I and -11 rescued apoptotic cells via a P13-K signaling pathway, not MAPK.
Data from this study lends further evidence to the significance of IGF proteins in the development in OSCC.